Currently, the abuse of heroin and prescription opioid medications is a pervasive social problem in the U.S. Similarly, the prevalence of tobacco use among adults in the U.S. is approximately 20%, despite intensive efforts to reduce its use. We are proposing to test the ability of pioglitazone, a peroxisome proliferator-activated receptor- gamma (PPAR) agonist that is FDA-approved for use in the management of type 2 diabetes mellitus, to reduce abuse of heroin (Study 1), and cigarette smoking (Study 2). Pioglitazone will be tested in combination with buprenorphine/naloxone (Study 1) and with the nicotine patch (Study 2). These studies were based on a series of unpublished preclinical data showing that pioglitazone may have utility in treating opioid and nicotine dependence. Participants in all studies will live on a locked inpatient unit and will be tested in the laboratory. The ability of pioglitazone to alter drug self-administration, reactivity to drug cues, and relapse to drug use will be assessed. In addition, subjective responses, such as ratings of drug liking, craving, and desire to take the drug again will be evaluated. Potential toxicity of the medication combinations will be assessed by measuring cognitive performance and physiological responses. The results of these studies will provide a great deal of information about the effects of pioglitazone in combination with agonist replacement therapies. If the results of the proposed studies support the preclinical data with pioglitazone, they may reveal a previously unidentified target for medications development for substance abuse.